Orally disintegrating tablets are tablets that disintegrate rapidly in the oral cavity even when taken without water, and are a preparation easily ingestible even by elderly people with decreased capability of swallowing.
In recent years, there have been active efforts at hospitals and dispensing pharmacies for improving drug compliance for patients taking a plurality of medicines by setting the plurality of medicines in a single package for each intake time zone to prevent the patient from failing to take a medicine, or from erroneously taking an incorrect medicine. For this reason, before the patient takes a medicine, the drug is sometimes exposed to moist conditions as is taken out from the package or PTP sheet. Because orally disintegrating tablets, in particular, generally have low tablet hardness, it is feared that the tablet can break before intake, or the disintegration time is delayed, if the tablet hardness decreases due to exposure to moist conditions. For this reason, there is a demand for the creation of an orally disintegrating tablet that undergoes minor hardness reduction and maintains disintegrability even when stored under moist conditions in medical practice settings.
An orally disintegrating tablet often contains a sugar alcohol used as an excipient to secure disintegrability. However, if the tablet ingredients contained in the orally disintegrating tablet include a substance that reacts with sugar alcohols to produce an impurity, it is desirable that the tablet ingredients be substantially free from sugar alcohols.
In this situation, regarding orally disintegrating tablets that do not contain sugar alcohols as essential ingredients, and that contain crystalline cellulose and anhydrous calcium hydrogen phosphate as excipients, Patent Documents 1 to 5 and Non-patent Document 1 shown below are known.
The orally disintegrating tablet described in Patent Document 1 consists essentially of an active ingredient, crystalline cellulose and an inorganic excipient such as anhydrous calcium hydrogen phosphate, and is characterized by the absence of a disintegrant. Furthermore, it is stated that the orally disintegrating tablet of Patent Document 1 is less likely to undergo hardness reduction and disintegration time delay under moist conditions, compared with orally disintegrating tablets containing a disintegrant such as crospovidone or croscarmellose sodium (Example 5 and Comparative Examples 5 to 9). There is another statement, “Because disintegrants have tablet quality deteriorating properties, such as causing tablet hardness reductions and tablet surface roughness as a result of moisture absorption, and worsening the mouth touch due to a feeling of dryness as a result of saliva absorption, the present invention, which does not contain a disintegrant, is advantageous.”
Described in Patent Document 2 is an orally disintegrating tablet containing an active ingredient, crystalline cellulose, an inorganic excipient such as anhydrous calcium hydrogen phosphate, carmellose and a lubricant at 0.8 wt % or less. In the orally disintegrating tablet, it is essential to use carmellose as a disintegrant, and the use of a disintegrant like natural starch as a disintegrant is not described at all.
Patent Document 3 relates to a rapidly disintegrating tablet containing a water-insoluble inorganic excipient, a disintegrant, and a substantially water-soluble excipient, and discloses an orally disintegrating tablet containing anhydrous calcium hydrogen phosphate, corn starch, crystalline cellulose and magnesium stearate. However, the blending ratio of anhydrous calcium hydrogen phosphate and the blending ratio of magnesium stearate in the orally disintegrating tablet differ from the blending ratio of a calcium hydrogen phosphate compound and the blending ratio of a lubricant in the orally disintegrating tablet of the present invention described below. Incidentally, the absolute hardness of the orally disintegrating tablet described in Patent Document 3 (tensile strength as determined by squashing in diameter direction) is 0.7 N/mm2 or less.
Disclosed in Patent Document 4 is a tablet containing crystalline cellulose, calcium hydrogen phosphate, corn starch, and magnesium stearate; the blending ratio of calcium hydrogen phosphate and the blending ratio of magnesium stearate differ from the blending ratio of a calcium hydrogen phosphate compound and the blending ratio of a lubricant in the orally disintegrating tablet of the present invention described below.
Patent Document 5 relates to a bitterness-suppressed preparation; disclosed in Example 34 thereof is a preparation containing granules obtained by agitation granulating an efficacy ingredient, corn starch and hydroxypropylmethylcellulose, crystalline cellulose, calcium hydrogen phosphate and magnesium stearate.
Described in Non-patent Document 1 is an orally disintegrating tablet containing crystalline cellulose, anhydrous calcium hydrogen phosphate, and, as a disintegrant, croscarmellose sodium or carmellose. However, the use of a natural starch as used in the present invention described below as a disintegrant is not described at all. Nor is there any description of the suppression of hardness reduction and disintegration time delay under moist conditions, which are the problems to be solved by the present invention described below.
Described in Patent Document 6 are a spray-dried composition of calcium hydrogen phosphate and erythritol, a composition for bitterness masking containing an umami ingredient, and an orally disintegrating tablet containing these compositions. Disclosed in an Example in the specification is an orally disintegrating tablet containing crystalline cellulose, calcium hydrogen phosphate, corn starch, and a lubricant at 1 wt % or less; however, the present invention described below, which does not contain erythritol as an essential ingredient, is distinct from the orally disintegrating tablet, for which it is essential to spray-dry a suspension of calcium hydrogen phosphate and erythritol. Furthermore, the invention described in Patent Document 6 intends to mask the bitterness of bitter ingredients, and the suppression of hardness reduction and disintegration time delay under moist conditions, which are the problems to be solved by the present invention described below, is not described at all.    Patent Document 1: WO2005/123040    Patent Document 2: WO2007/018192    Patent Document 3: JP-A-2002-505269    Patent Document 4: JP-A-HEI-5-32627    Patent Document 5: WO2007/018190    Patent Document 6: JP-A-2001-69961    Non-patent Document 1: Pamphlet by Kyowa Chemical Industry Co. Ltd. (Report on anhydrous calcium hydrogen phosphate GS)